目的 應(yīng)用食蟹猴重復(fù)給藥毒性伴隨安全藥理學(xué)研究的實(shí)例，探究利用無創(chuàng)遙測技術(shù)進(jìn)行伴隨于重復(fù)給藥毒性試驗(yàn)的心血管、呼吸系統(tǒng)安全藥理學(xué)研究的可行性。方法 重復(fù)給藥毒性試驗(yàn)取食蟹猴40只（雌雄各半，其中32只進(jìn)行安全藥理學(xué)研究），分為4組，即空白對照組、佐劑對照組和四價重組諾如病毒疫苗（畢赤酵母）低、高劑量組，分別為不給任何受試物，每次im佐劑對照品1 mL（2人份）/猴、四價重組諾如病毒疫苗（畢赤酵母）0.5 mL（1人份）/猴和1 mL（2人份）/猴，每4周給藥1次，共給藥4次。食蟹猴經(jīng)穿脫馬甲和猴椅固定的適應(yīng)性訓(xùn)練后開始正式試驗(yàn)；安全藥理學(xué)試驗(yàn)數(shù)據(jù)的采集安排在首次與第3次給藥時，使用馬甲式遙測系統(tǒng)采集給藥后0~24 h的呼吸、心電、體溫等相關(guān)參數(shù)，并增加采集給藥后0~2、5~6、23~24 h時間段的血壓數(shù)據(jù)（將猴保定在猴椅上）。結(jié)果 單次及3次給予四價重組諾如病毒疫苗（畢赤酵母）低、高劑量以及佐劑對照品對食蟹猴呼吸、心電、血壓、體溫等各項(xiàng)指標(biāo)均未見明顯影響。部分時段的指標(biāo)波動均屬猴正常的應(yīng)激（受束縛狀態(tài)下）變化或晝夜生理節(jié)律性變化。結(jié)論 在本試驗(yàn)劑量條件下，單次及多次im四價重組諾如病毒疫苗（畢赤酵母），對食蟹猴呼吸系統(tǒng)、心血管系統(tǒng)均未見明顯影響；利用馬甲式無創(chuàng)遙測系統(tǒng)結(jié)合重復(fù)給藥毒性試驗(yàn)進(jìn)行安全藥理學(xué)研究（心血管、呼吸系統(tǒng)）具有良好的可行性，符合動物福利3R原則，尤其適合于重復(fù)給藥后的安全藥理學(xué)研究。

Objective The feasibility of the study of cardiovascular and respiratory safety pharmacology using non-invasive telemetry technology combined with repeated toxicity test was explored by the example of safety pharmacology study in cynomolgus monkeys. Methods As a case, this study observed the effects of quadrivalent recombinant norovirus vaccine (pichia pastoris), on the respiratory and cardiovascular systems in conscious cynomolgus monkeys combining with the repeat-dose toxicity test of quadrivalent recombinant norovirus vaccine (pichia pastoris). A total of 40 cynomolgus monkeys were used for repeat-dose toxicity test, 32 of them were subjected to safety pharmacology study. Animals were divided into four groups, namely blank control group, adjuvant control group, low dose group and high dose group of quadrivalent recombinant norovirus vaccine (pichia pastoris). Animals in blank control group did not administrate any article, and those in other three groups were intramuscularly injected with adjuvant 1 mL (2 human dose)/monkey, quadrivalent recombinant norovirus vaccine (pichia pastoris) 0.5 mL (1 human dose)/monkey, 1 mL (2 human dose)/monkey, once every 4 weeks, a total of 4 times for repeat-dose toxicity test. The cynomolgus monkeys began formal testing after the adaptive training of wearing the vest and fixed in the monkey chair. The data of safety pharmacology test were collected on the first and third administration, and the parameters of respiration, electrocardiogram, body temperature from 0 to 24 hours after administration were collected using the telemetry system, and the data of blood pressure in period of 0-2, 5-6, 23-24 hours after administration were collected for the monkey fixed on the monkey chair. Results The first and third administration of quadrivalent recombinant norovirus vaccine (pichia pastoris), in low or high dose, or adjuvant control all had no significant effect on the respiratory, electrocardiogram, blood pressure and body temperature in cynomolgus monkeys. The fluctuation of the few indexes in some periods was related to the normal stress in the state of restraint or the circadian rhythm of the monkey. Conclusion Under the conditions of this test, single or multiple intramuscular injections of preventive biologics quadrivalent recombinant norovirus vaccine (pichia pastoris) had no significant effect on the respiratory and cardiovascular system in cynomolgus monkeys. It is feasible to perform a safety pharmacology study combined with a repeat-dose toxicity test using a noninvasive telemetry system, which would be following animal welfare 3R principle, especially be suitable for safety pharmacology studies after multiple administration.

R965.3

浙江省科技計(jì)劃項(xiàng)目（2017F10001）